Ideally, implants should be designed with the ability to promote specific biological responses. In the case of bone-contacting materials, this would mean that, immediately following implantation, the devices would induce cells of the osteoblastic lineage to form bone on or in close proximity to the biomaterial. Stable fixation of the implant and better integration into the tissue would be the result. The overall goal of this research is to develop biomolecular surface modification strategies that induce specific cell and tissue responses. For example, stimulation of tissue regeneration, in which the implant becomes integrated into the tissue, is more desirable than repair, in which the implant is generally walled off with a fibrous capsule. It is postulated that bone-contacting materials possessing surfaces with osteotropic biomolecules in a specific presentation can control initial cellular events at the tissue-biomaterial interface. In Specific Aim 1, bis-hydrazide-derivatized poly(D,L-lactide-co-glycolide) coatings, microspheres, and porous scaffolds will be developed for use in site-directed immobilization of osteotropic growth factors. Surfaces with different lengths and surface densities of bis-hydrazide molecules will be produced. In Specific Aim 2, rational schemes will be designed and implemented for site-directed immobilization of growth factors on the materials developed in Aim 1. Recombinant DNA techniques will be used to introduce modifications to the amino termini of insulin-like growth factor I and bone morphogenetic protein 2. These unique sites will allow the growth factors to be immobilized in an orientation that maximizes interaction with cell surface receptors. In Specific Aim 3, in vitro and in vivo biological activity of the rationally modified biomaterials will be determined. Cell cultures will also be used to assess activation of the appropriate cell surface receptors by the immobilized growth factors. It is hypothesized that site-directed immobilization of growth factors will yield higher specific bioactivity and, therefore, will result in greater cell and tissue responses (specifically bone formation) compared to randomly immobilized protein. The findings of these studies will impact the development of bone-contacting biomaterials having the ability to induce desired interracial responses.